The immunosuppressant drugs cyclosporin A and FK506 are thought to exert their therapeutic effects by binding to receptor proteins, designated cyclophilins and FK506 binding proteins (FKBP) respectively. When complexed to the immunosuppressant drugs, these binding proteins, designated immunophilins, bind to the Ca.sup.2+ activated phosphatase, calcineurin, to inhibit its activity and increase levels of phosphorylated calcineurin substrate proteins (1-9). Concentrations of the immunophilins are far higher in the brain and peripheral nervous system than in immune tissues, and FKBP is co-localized with calcineurin throughout the brain, suggesting an important functional relationship (4).
We recently showed that cyclosporin A and FK506 block the neurotoxicity elicited by glutamate acting at N-methyl-D-aspartate (NMDA) receptors in cerebral cortical cultures (10). The mechanism for the neuroprotective effects of these drugs appears to be inhibition of calcineurin with an augmentation of phosphorylated levels of nitric oxide synthase (NOS) (10). Since phosphorylation of NOS inhibits its catalytic activity (11), the immunosuppressants effectively reduce nitric oxide (NO) formation, preventing the neurotoxic effects of NMDA in these cultures (12,13).
GAP43 is a prominent protein in neuronal processes associated with neurite extension and is also a major calcineurin substrate (14). Regeneration of damaged facial and sciatic nerves is associated with a marked augmentation of GAP43 mRNA levels (15-18).
There is a need in the art for methods of stimulating neuronal cells growth, especially in the case of nerve damage by physical injury or disease. Stimulation of neuronal growth allows a quicker and more complete recovery of damaged nerves.